This Clinical Trials project will evaluate several innovative, personalized and adaptive approaches to smoking cessation treatment. We developed and validated the first evidence-based algorithm for tailoring smoking cessation treatment to smokers? baseline characteristics and their initial therapeutic response to treatment with our previous 4 years of NIDA support. We will build on this progress by exploring three novel therapeutic approaches that seek to benefit the following distinct populations of smokers: 1) women concerned about weight gain after quitting smoking, who have been shown in previous studies to be especially prone to relapse after quitting smoking. We will evaluate the efficacy of lorcaserin, a 5-HT2C agonist that is FDA-approved for weight loss, which has been shown by our Center?s Preclinical Studies to reduce nicotine self-administration. A sample of women concerned about post-cessation weight gain will be randomized to receiving lorcaserin vs. placebo capsules; 2) smokers for whom the inhalational aspects of smoking are important, a need that is not well addressed by conventional nicotine replacement therapy (NRT). Electronic nicotine delivery systems (?ENDS?) provide replacement of both nicotine and key inhalational aspects of smoking behavior and have shown promise in smoking cessation treatment. In a sample of smokers who report inhalational aspects of smoking to be important to them, we will evaluate the efficacy of ENDS alone or in combination with NRT compared to NRT alone; and 3) smokers who express concern about negative mood consequences of quitting smoking, which confers greater risk of relapse. In these smokers, we will evaluate the efficacy of amitifadine, a triple serotonin-norepinephrine-dopamine reuptake blocker that has antidepressant effects. Amitifadine has also been found in our Center?s Preclinical Studies to reduce nicotine self-administration. Smokers will be randomized into three groups receiving one of the two active doses of amitifadine or placebo. In each of the above clinical trials, participants will be evaluated after the first week of treatment, using a laboratory-based paradigm to identify and validate early markers of treatment outcome. These measures include ad lib smoking, mood, craving and withdrawal symptoms, and the ability to refrain from smoking in a simulated smoking lapse paradigm. We will correlate treatment outcome with these measures of the initial response to treatment. Additionally, we will correlate abstinence outcomes with smokers? baseline characteristics, including demographic variables, smoking history, and genetic markers identified in prior studies. By validating markers predictive of treatment outcome, we will both facilitate the rapid screening of novel candidate treatments and help identify which treatments will be most likely to help specific subpopulations of smokers achieve long-term smoking abstinence. Together with evaluating the efficacy of the candidate treatments described above, this project will likely contribute valuable new therapeutic approaches and a framework to help guide their dissemination to targeted subpopulations of smokers.